Targeted delivery of antibody bound to antigen is a precise drug delivery mode. It is regarded as one of the ideal targeted drug delivery modes due to its high specificity and affinity, which opens up a new way to successfully solve the problem of poor selectivity of chemotherapy drugs in antitumor therapy. Currently, the research on antibody drug conjugates(ADCs) that bind monoclonal antibodies to target antigens has become a research hotspot of molecular targeted therapy. This paper reviews the mechanism of action, targeting strategies and progress in the targeted delivery of ADCs, in order to provide reference for the clinical development of new ADCs.

Ameloblastoma is a benign tumor characterized by locally invasive phenotypes,leading to facial bone destruction and a high recurrence rate.However,the mechanisms governing tumor initiation and recurrence are poorly understood.Here,we uncovered cellular landscapes and mechanisms that underlie tumor recurrence in ameloblastoma at single-cell resolution.Our results revealed that ameloblastoma exhibits five tumor subpopulations varying with respect to immune response(IR),bone remodeling(BR),tooth development(TD),epithelial development(ED),and cell cycle(CC)signatures.Of note,we found that CC ameloblastoma cells were endowed with stemness and contributed to tumor recurrence,which was dominated by the EZH2-mediated program.Targeting EZH2 effectively eliminated CC ameloblastoma cells and inhibited tumor growth in ameloblastoma patient-derived organoids.These data described the tumor subpopulation and clarified the identity,function,and regulatory mechanism of CC ameloblastoma cells,providing a potential therapeutic target for ameloblastoma.

Objective:To evaluate the safety, efficacy and performance of disposable cholangiopancreatoscope in the diagnosis and treatment of bile duct diseases.Methods:A total of 20 subjects were selected and 16 subjects were enrolled in the prospective and exploratory clinical study which were performed in the Digestive Endoscope Center of Hangzhou First People's Hospital Affiliated to Zhejiang University School of Medicine from July 2021 to August 2021. The disposable cholangiopancreatoscope was used to diagnose bile duct diseases in routine endoscopic retrograde cholangiopancreatography. Biopsies were performed in cases where malignancy was considered. The use related indexes and performance indexes of the instruments were analyzed.Results:Among the 16 patients, there were 6 cases of biliary space-occupying lesions, 6 cases of biliary calculi, and 4 cases of benign biliary stricture before operation. The success rate of the disposable insertion was 100.00% (16/16), and the success rate of observation was 100.00% (16/16). Three biliary space-occupying lesions diagnosed as malignant tumor under cholangiopancreatoscope were confirmed by pathology after operation. Diagnosis of other patients was consistent with preoperative diagnose, so no biopsy was conducted. The rate of positive feedback from operators in directional control was 81.25% (13/16), the image failure rate was 18.75% (3/16), and the rate of positive feedback for image clarity was 93.75% (15/16). In terms of clinical performance, the imaging quality of excellence was 93.75% (15/16), the flexible degree of excellence was 81.25% (13/16), and other indexes were all 100.00% excellence. During the period, there were no instrument defects, pancreatitis, perforation, bleeding or other instrument-related adverse events.Conclusion:The effectiveness, safety and performance indexes of domestic disposable cholangiopancreatoscope have reached the standards of clinical application with high pixel, integration, and portability. It's worthy of clinical recommendation.

Objective:To evaluate the efficacy of angioplasty on percutaneous superior vena cava occlusion in hemodialysis patients with tunnel-cuffed catheter (TCC) under digital subtraction angiography (DSA) guidance.Methods:A total of 62 hemodialysis patients with TCC in the First Affiliated Hospital of Sun Yat-sen University from December 2017 to June 2020 were enrolled retrospectively. According to the patency of the superior vena cava, the patients were divided into experiment group ( n=20) and control group ( n=42) in this study. Hemodialysis patients with superior vena cava occlusion in the experiment group received angioplasty, including balloon angioplasty, stenting and sharp recanalization, and catheterization with TCC under DSA guidance, while hemodialysis patients without superior vena cava occlusion in the control group only underwent catheterization with TCC under DSA guidance. The 1-year TCC patency rate, postoperative TCC blood flow and treatment-related complications between the two groups were compared. Results:In the experiment group, a total of 11 patients were treated only by percutaneous transluminal angioplasty, while 9 patients were treated combined percutaneous transluminal angioplasty with stent placement. In addition, 3 patients underwent sharp recanalization of superior vena cava occlusion. A total of 9 stents and 29 balloons were used. The course of dialysis in experiment group was longer than that in control group ( P<0.05). There were no significant differences in the 1-year TCC patency rate (85.0% vs 95.2%, P>0.05), postoperative TCC blood flow [(257.83±16.55) ml/min vs (251.90±18.79) ml/min, P>0.05] and incidence of treatment-related complications (grade 1-2, 30.0% vs 35.7%, P>0.05) between the two groups, respectively. Patients in the two groups had none of serious operation-related complications, and only some patients had mild clinical manifestations, such as postoperative pain and bleeding at the puncture point. Conclusions:For patients with longer duration of hemodialysis and superior vena cava stenosis and occlusion treated with angioplasty, the clinical effect of TCC within one year is equivalent to that of hemodialysis patients without angioplasty.

OBJECTIVETo provide a theoretical basis for surface modification of titanium implants, the effects of the stiffness of polyelectrolyte multilayer films on titanium surface on bacterium adhesion was explored.

METHODSVia layer-by-layer technique, catechol functionalized polyelectrolyte multilayer film (cPEM) was constructed on titanium surface by using catechol functionalized hyaluronic acid (cHA) and lipopolysaccharide-amine nanopolymersomes (NP). The stiffness of cPEM was controlled by adjusting the catechol substitution degree of cHA (5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%). Titanium samples covered with cPEM were selected as test group, and the cPEM was constructed with the lowest, medium and highest stiffness. The polished titanium was used as a control. The surface topography of titanium before and after film construction was observed by scanning electron microscopy (SEM). At 1 and 24 h after incubation, the adhesion and clonal formation of Streptococcus mutans (S. mutans) on different titanium surfaces were quantified, and their morphology and survival status were observed by SEM and laser scanning confocal microscope (LSCM).

RESULTSWhen the catechol grafting ratio was 5%, 30% and 70%, the lowest, medium and highest cPEM stiffness were obtained, and the cPEM stiffness were (10.69±4.54) GPa(cPEM-L), (20.99± 5.81) GPa (cPEM-M) and (32.57±6.93) GPa (cPEM-H) respectively, and the stiffness of polished titanium was (107.12±8.68) GPa (P<0.05). SEM observation showed that after cPEM coating, the titanium surface became smoother. After incubation for 1 and 24 h, the amount of adhesion and clonal formation of S. mutans on cPEM were higher than those on control titanium, and the difference was statistically significant (P<0.05). SEM images showed that for 1 h incubation, softer surfaces were beneficial for S. mutans adhering and agglomerating, while this difference nearly disappeared at 24 h. Observation under LSCM revealed that most of bacteria were alive on titanium disks at 1 h, and their amount decreased with the increase of stiffness. At 24 h, the living/dead bacterium ratios on cPEM-L and control titanium was higher than that on cPEM-M and cPEM-H, and cPEM-L surface was dominated by living bacteria, while stiffer cPEM-M and cPEM-H had more dead bacteria than living bacteria.

CONCLUSIONSIncreasing the stiffness of polyelectrolyte films on titanium limits the adhesion of S. mutans. As an independent factor, stiffness influences the bacterium adhesion.

Bacterial Adhesion ; Catechols ; Elasticity ; Hyaluronic Acid ; Lipopolysaccharides ; Microscopy, Confocal ; Microscopy, Electron, Scanning ; Nanoparticles ; Polymers ; chemistry ; Streptococcus mutans ; physiology ; Surface Properties ; Time Factors ; Titanium ; chemistry

OBJECTIVETo explore biomimetic mineralization of polyelectrolyte multilayer films (PEM) of gene-loaded lipopolysaccharide-amine nanopolymersomes/hyaluronic acid self assembled on titanium surface.

METHODSVia lay-by-layer self assembly technology, PEM were constructed on titanium or quartz surface using bone morphogenetic protein-2(BMP-2) plasmid-loaded lipopolysaccharide-amine nanopolymersomes(pLNP) as a polycation, and hyaluronic acid(HA) as a polyanion. The constructed PEM were defined as substrate-pLNP-(HA-pLNP)n, where a successive deposition of HA and pLNP on substrate surface was defined as one assembly cycle, and n was the cycle number. Biomimetic mineralization on surfaces of Ti-pLNP-(HA-pLNP)4(Group A, with outermost layer of pLNP), Ti-pLNP-(HA-pLNP)4.5(Group B, with outermost layer of HA), blank control(polished titanium, Ti) and alkaline-heat treated titanium(Ti-OH) were investigated. The biomimetic mineralization was analyzed by observing the topography under field-emisssion electron microscopy(FE-SEM), characterizing the surface chemical structure and components via X-ray diffractometer(XRD) and X-ray energy disperse spectroscopy(EDS).

RESULTSFor experiment groups, XRD analysis showed that the diffraction peak of hydroxyapatite appeared, and its intensity was higher than that for Ti group. FE-SEM images showed that its surface was homogeneously covered by discrete agglomerate of big particles. EDS spectra showed that the percentage of Ca and P were 77.24% and 64.23%, and these were much higher than those in Ti group.

CONCLUSIONSThe surface of Ti-pLNP-(HA-pLNP)n is favorable for in vitro biomimetic mineralization.

Amines ; chemistry ; Biomimetic Materials ; chemistry ; Bone Morphogenetic Protein 2 ; Durapatite ; chemistry ; Hyaluronic Acid ; chemistry ; Lipopolysaccharides ; Nanocomposites ; chemistry ; Plasmids ; Surface Properties ; Titanium ; chemistry

OBJECTIVE To investigate the effect and related mechanism of all￣trans retinoic acid (atRA) exposure on osteogenic differentiation of mouse embryonic palate masenchymal cells MEPM. METHODS MEPM were cultured in osteogenic medium (OM) with atRA 0.1 and 1.0 μmol??L-1 for 1, 3,5, 7 and 9 d. MTT assay was performed to measure the cell viability. The alkaline phosphatase (ALP) activity was measured by chemical colorimetry. The cells were stained using the Von￣Kossa technique to detect the formation of mineralization nodules after 21 d of culture. RT￣PCR was performed to determine expression Runx2, osteopontin, bone morphogenetic protein receptor ( Bmpr) 1b, Bmpr2 and Smad5 mRNA. RESULTS The result of MTT on 9 d showed that, compared with normal control group, the cell viability of OM, OM+atRA 0.1 and 1.0 μmol??L-1 groups decreased significantly(P<0.01). Compared with normal control group, ALP activity of OM group increased significantly(P<0.05), while the ALP activity of OM+atRA 0.1 and 1.0 μmol??L-1 groups was lower than OM group(P<0.05). On 21 d, the Von￣Kossa stai￣ning results showed that the percentage of mineralization nodules formation of OM+atRA 1.0 μmol??L-1 group was (3.65±1.24)%, which was significantly lower than that of OM group(10.33±2.29)%(P<0. 05). On 9 d, the relative Run expression of OM group was the highest one in the four groups, while at￣RA 1.0 μmol??L-1 treatment negatively regulated 20% in comparsion with OM group(P<0.05). Compared with normal control group, the mRNA expression of osteopontin of OM, OM+atRA 0.1 and 1.0 μmol??L-1 groups increased significantly(P<0.05); BDNF mRNA expression of OM group was 2.6￣fold to normal control group, while that of OM+atRA 1.0 μmol??L-1 group was 33% to OM group(P<0.05) . The level of Smad5 mRNA of OM+atRA 1.0 μmol??L-1 group was significantly lower than that of OM group(P<0.05). CONCLUSION atRA Might inhibit osteogenic differentiation of MEPM by down￣regulated the expression of Bmpr1b.

OBJECTIVETo investigate the effects of all-trans retinoic acid (atRA) on the function of bone morphogenetic protein receptor 2 (BMPR2) expression in embryonic palate.

METHODSCleft palate mice model was established by atRA. On gestation day (GD) 15 and GD 17, the pregnant mice were killed to obtain the embryos from the uteri. The embryonic palates were stained with hematoxylin-eosin, and the remaining sections were used for the immunohistochemistry of BMPR2 detection. Reverse transcription-polymerase chain reaction was performed to detect the expression levels of Bmpr2 mRNA.

RESULTSIn the atRA-treated group, short extensions and failure to fuse with each other were observed. The positive expression of BMPR2 was detected in developing palatal process from GD 15 to GD 17 in the control group. Compared with those of the control group, BMPR2 protein and Bmpr2 mRNA decreased in the atRA-treated group (P<0.05).

CONCLUSIONThe treatment of pregnant mice with retinoic acid produces small palatal shelves in their fetuses and down-regulates BMPR2 expressions.

Animals ; Bone Morphogenetic Protein 2 ; Cleft Palate ; Disease Models, Animal ; Down-Regulation ; Female ; Mice ; Pregnancy ; RNA, Messenger ; Tretinoin

Objective:To study the influence of all-trans retinoic acid (atRA)on craniomaxillofacial development of C57 mice. Methods:Pregnant C57BL mice were divided into 4 groups(n =5)at gestation day (GD)1 0.Mice in three atRA-induction groups were given atRA of 60,80 and 1 00 mg/kg,respectively.The mice in control group were given the equivalent volume of corn oil.All pregnant mice were sacrificed at GD1 9 and the embryos were collected.Stereo microscope was used to observe the craniomaxillofacial morphology.Standardized radiographs were taken and cephalometric analysis was performed.Results:The embryonic body length and body mass of control group surpassed those of 80 and 1 00 mg/kg atRA groups(P <0.05,P <0.01 ).atRA induced craniomaxillofacial malformations and maldevelopment.The mice induced by atRA exhibited a shorter mandibular body and more retrusive position of max-illary and mandibular(∠NAK and ∠NBD)when compared with their norm(P <0.01 ).Significant decrease in craniofacial length (Op-Rh)was observed in all atRA-induced groups(P <0.01 ).Decreases in cranial vault height(Fp-Os)and cranial vault length(Pa-Na)dimensions were observed in 80 and 1 00 mg/kg atRA groups(P <0.05,P <0.01 ).Conclusion:Exogenous atRA dose-depend-ently induces retardation of craniomaxillofacial morphology in embryo of C57BL mice by inhibition of the sagital and vertical dimension development of the bone.

Objective To?investigate?the?effects?of?all-trans?retinoic?acid?(atRA)?on?the?function?of?bone?morphogenetic?protein?receptor?2?(BMPR2)?expression?in?embryonic?palate.?Methods???Cleft?palate?mice?model?was?established?by?atRA.?On?gestation?day?(GD)?15?and?GD17,?the?pregnant?mice?were?killed?to?obtain?the?embryos?from?the?uteri.?The?embryonic?palates?were?stained?with?hematoxylin-eosin,?and?the?remaining?sections?were?used?for?the?immunohistochemistry?of?BMPR2?detection.?Reverse?transcription-polymerase?chain?reaction?was?performed?to?detect?the?expression?levels?of?Bmpr2?mRNA.?Results???In?the?atRA-treated?group,?short?extensions?and?failure?to?fuse?with?each?other?were?observed.?The?positive?expression?of?BMPR2?was?detected?in?developing?palatal?process?from?GD?15?to?GD?17?in?the?control?group.?Compared?with?those?of?the?control?group,?BMPR2?protein?and?Bmpr2?mRNA?decreased?in?the?atRA-treated?group?(P<0.05).?Conclusion???The?treatment?of?preg-nant?mice?with?retinoic?acid?produces?small?palatal?shelves?in?their?fetuses?and?down-regulates?BMPR2?expressions.